PROJECT SUMMARY Impaired neurogenesis accelerates cognitive decline under neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. Aging and associated inflammatory brain milieus suppress neurogenesis, yet the cause of inflammation is incompletely understood. Our continuing goal is to restore neurogenesis in aging and degenerative brains by elucidating the underlying mechanisms of its decline. Previously, we and others have demonstrated that FOXO integrates extracellular signals to regulate neurogenesis during mammalian aging. Our more recent studies indicate that FOXO plays a key role in connecting aging-related stress responses to inflammatory gene expressionin the brain. Inhibition of FOXO3 strongly attenuates stress-induced pro- inflammatory response. We therefore hypothesize that aging-associated integrated stress response (ISR) induces pro-inflammatory responses and subsequently suppresses neurogenesis through aberrant FOXO activation. We reason that targeting this process should delay molecular aging of neural stem/progenitor cells (NSPC) and boost neurogenesis. This competitive renewal will focus on testing the above hypothesis. In Aim1, we will define the mechanism underlying ISR-mediated FOXO3 activation in the brain. We will genetically test whether FOXO3 is a key downstream ISR effector by comparing in vivo neurogenesis in control and FOXO3 null NSPC-targeted ISR mouse models and also determine the functional role of USP9x-mediated FOXO3 deubiquitination in ISR-induced FOXO3 upregulation. In Aim2, we will elucidate how aberrant FOXO3 activation drives inflammation and defective neurogenesis. We will employ an inducible FOXO3 mouse model to determine in vivo effect of aberrant FOXO3 activation on NSPC nuclear structure and cGAS-STING- mediated pro-inflammatory responses. We will perform gain- or loss of function approaches to determine the function of FOXO3 activation-associated SAMe depletion on prelamin processing and cGAS-STING pathway activation. In Aim3, we will determine the in vivo effect of suppressing nuclear degeneration-induced inflammation on neurogenesis. We will also determine whether restoration of SAMe level by FOXO3 deletion or dietary SAMe supplement attenuates the impact of ISR on neurogenesis. In parallel, we will perform genetic or pharmacological inhibition of cGAS/STING-dependent type I IFN pro-inflammatory response condition in order to restore neurogenesis under ISR. In summary, completion of proposed study will not only elucidate a major pathological cause of aging- and other neurodegenerative diseases-related neurogenesis and cognitive decline, but also stimulate the development of new therapeutic targets and approaches to combat aging- related diseases.